Opioid Self-administration in the Nerve-injured Rat

2007 ◽  
Vol 106 (2) ◽  
pp. 312-322 ◽  
Author(s):  
Thomas J. Martin ◽  
Susy A. Kim ◽  
Nancy L. Buechler ◽  
Frank Porreca ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Intrathecal Administration ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Drug Intake ◽  
Spontaneous Pain ◽  
Self Administration ◽  
Mechanical Hypersensitivity ◽  
Opioid Sparing

Background Neuropathic pain is associated with several sensory abnormalities, including allodynia as well as spontaneous pain. Opioid intake in neuropathic pain patients is motivated by alleviation of both pain and allodynia. However, laboratory animal studies rely almost exclusively on reflexive withdrawal measures of allodynia. The authors examined the pharmacology of self-regulated intake of opioids in rats with or without nerve injury and compared the rate of drug intake to reversal of allodynia. Methods Rats were implanted with intravenous catheters, and the L5 and L6 spinal nerves were ligated in half of these animals. Rats were then trained to self-administer a commonly abused opioid (heroin) and commonly prescribed opioids (morphine, fentanyl, hydromorphone, and methadone). In addition, rats trained to self-administer heroin were given either clonidine or adenosine spinally before self-administration sessions to assess opioid-sparing effects. Results Nerve injury significantly decreased the reinforcing effects of low doses of opioids, and only doses of each opioid that reduced mechanical hypersensitivity maintained self-administration after spinal nerve ligation. The rate of drug consumption was correlated with the duration of the antiallodynic effect for each dose of opioid. Intrathecal administration of clonidine or adenosine reversed mechanical hypersensitivity, but only clonidine reduced heroin self-administration in rats with spinal nerve ligation. Conclusion Opioid self-administration is significantly altered by nerve injury, with rate of drug intake being correlated with reversal of allodynia. Intrathecal clonidine, but not adenosine, produces opioid-sparing effects in self-administering rats. The neurobiologic mechanisms that regulate opioid consumption in rats therefore seem to be altered after nerve injury.

scholarly journals The Effect of Epidural Resiniferatoxin in the Neuropathic Pain Rat Model

2012 ◽  
Vol 4;15 (4;8) ◽  
pp. 287-296
Author(s):  
Mi Kyoung Lee
Keyword(s):  
Neuropathic Pain ◽  
Rat Model ◽  
Analgesic Effect ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Thermal Stimulation ◽  
Control Group ◽  
Transient Receptor Potential Vanilloid ◽  
Epidural Administration ◽  
Mechanical Hypersensitivity

Background: Resiniferatoxin (RTX) is a potent synthetic agonist for transient receptor potential vanilloid subtype 1 (TRPV1), which has a selectivity for antinociception. The analgesic effect of epidural RTX in a rat model of neuropathic pain has not yet been studied. Objectives: The purpose of this study was to evaluate the analgesic effect of epidural RTX on neuropathic pain in a rat model to mechanical and thermal stimulation. The dose-related behavior changes and side effects were also studied. Study design: A randomized, experimental trial. Setting: Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital Methods: A spinal nerve ligation model was prepared using male Sprague-Dawley rats (7 weeks old, weight 230-250 g). An epidural catheter was placed at the L4-L5 level. Each study group (n = 6) received a different dose of RTX: 100 ng, 500 ng, 1 µg, 2 µg, 4 µg and 10 µg. All substances were administered in 20 µL volume doses. The control group (n = 6) received 20 µL of normal saline. We evaluated the response to mechanical and thermal stimuli as well as the sedation score at both short-term (3 hours) and long-term (20 days) after the epidural RTX injection. Results: Prolonged analgesia to thermal stimulation was preceded by a transient dose-dependent hyperalgesia (500 ng, 1 µg) or sedation (≥ 2 µg) during the initial 60 minutes after RTX administration. Marked sedation and hyperventilation were noted at higher doses (≥ 2 µg), while 2 out of 6 rats died with a 10 µg dose. ED50 for epidural RTX was 265 ng (95% confidence interval 216.1–324.9 ng). The increased latency to thermal stimulation continued for 20 days at RTX ≥ 1 µg. But the threshold to mechanical stimulation increased only in the acute period and returned to the baseline after 3-5 days, regardless of the administered dose. Limitations: A histological examination by electron-microscopic staining was not performed. The observation period was not very long (20 days). Conclusion: RTX has potential to be used in an epidural route for neuropathic pain in a rat model with a relatively small amount, which produces transitory improvement of mechanical hypersensitivity and prolonged thermal analgesic response. Key words: Epidural administration, mechanical allodynia, mechanical hypersensitivity, resiniferatoxin, sedation, spinal nerve ligation rat model, thermal hyperalgesia.

Cyclooxygenase-1 in the Spinal Cord Is Altered after Peripheral Nerve Injury

2003 ◽  
Vol 99 (5) ◽  
pp. 1175-1179 ◽  
Author(s):  
Xiaoying Zhu ◽  
James C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Male Rats ◽  
Dependent Manner ◽  
Cyclooxygenase 1 ◽  
Cox 1

Background The mechanisms underlying neuropathic pain are incompletely understood and its treatment is often unsatisfactory. Spinal cyclooxygenase-2 (COX-2) expression is upregulated after peripheral inflammation, associated with spinal prostaglandin production leading to central sensitization, but the role of COX isoenzymes in sensitization after nerve injury is less well characterized. The current study was undertaken to determine whether COX-1 was altered in this model. Methods Male rats underwent partial sciatic nerve transsection (PSNT) or L5-L6 spinal nerve ligation (SNL). Four weeks after PSNT and 4 h, 4 days, or 2 weeks after SNL, COX-1 immunohistochemistry was performed on the L2-S2 spinal cord. Results COX-1 immunoreactivity (COX-1-IR) was unaffected 4 h after SNL. In contrast, 4 days after SNL, the number of COX-1-IR cells increased in the ipsilateral spinal cord. COX-1-IR increased in cells with glial morphology in the superficial laminae, but decreased in the rest of the ipsilateral spinal cord 4 weeks after PSNT and 2 weeks after SNL. These changes in immunostaining were greatest at the L5 level. Conclusion These data suggest that COX-1 expression in the spinal cord is not static, but changes in a time- and laminar-dependent manner after nerve injury. These anatomic data are consistent with observations by others that spinally administered specific COX-1 inhibitors may be useful to prevent and treat neuropathic pain.

scholarly journals Involvement of the Lateral Amygdala in the Antiallodynic and Reinforcing Effects of Heroin in Rats after Peripheral Nerve Injury

2011 ◽  
Vol 114 (3) ◽  
pp. 633-642 ◽  
Author(s):  
Thomas J. Martin ◽  
Nancy L. Buechler ◽  
Susy A. Kim ◽  
Eric E. Ewan ◽  
Ruoyu Xiao ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Opioid Receptors ◽  
Peripheral Nerve Injury ◽  
Spinal Nerve ◽  
Self Administration ◽  
Lateral Amygdala ◽  
Reinforcing Effects ◽  
Μ Opioid Receptors

Background Neuropathic pain alters opioid self-administration in rats. The brain regions altered in the presence of neuropathic pain mediating these differences have not been identified, but likely involve ascending pain pathways interacting with the limbic system. The amygdala is a brain region that integrates noxious stimulation with limbic activity. Methods μ-Opioid receptors were blocked in the amygdala using the irreversible antagonist, β-funaltrexamine, and the antiallodynic and reinforcing effects of heroin were determined in spinal nerve-ligated rats. In addition, the effect of β-funaltrexamine was determined on heroin self-administration in sham-operated rats. Results β-Funaltrexamine decreased functional activity of μ-opioid receptors by 60 ± 5% (mean ± SD). Irreversible inhibition of μ-opioid receptors in the amygdala significantly attenuated the ability of doses of heroin up to 100 μg/kg to reverse hypersensitivity after spinal nerve ligation. Heroin intake by self-administration in spinal nerve-ligated rats was increased from 5.0 ± 0.3 to 9.9 ± 2.1 infusions/h after administration of 2.5 nmol of β-funaltrexamine in the lateral amygdala, while having no effect in sham-operated animals (5.8 ± 1.6 before, 6.7 ± 0.9 after). The antiallodynic effects of 60 μg/kg heroin were decreased up to 4 days, but self-administration was affected for up to 14 days. Conclusions μ-Opioid receptors in the lateral amygdala partially meditate heroin's antiallodynic effects and self-administration after peripheral nerve injury. The lack of effect of β-funaltrexamine on heroin self-administration in sham-operated subjects suggests that opioids maintain self-administration through a distinct mechanism in the presence of pain.

Proteomics study of neuropathic and nonneuropathic dorsal root ganglia: altered protein regulation following segmental spinal nerve ligation injury

2007 ◽  
Vol 29 (2) ◽  
pp. 215-230 ◽  
Author(s):  
Naoka Komori ◽  
Nobuaki Takemori ◽  
Hee Kee Kim ◽  
Anil Singh ◽  
Seon-Hee Hwang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Proteomics Study

Peripheral nerve injury is often followed by the development of severe neuropathic pain. Nerve degeneration accompanied by inflammatory mediators is thought to play a role in generation of neuropathic pain. Neuronal cell death follows axonal degeneration, devastating a vast number of molecules in injured neurons and the neighboring cells. Because we have little understanding of the cellular and molecular mechanisms underlying neuronal cell death triggered by nerve injury, we conducted a proteomics study of rat 4th and 5th lumbar (L4 and L5) dorsal root ganglion (DRG) after L5 spinal nerve ligation. DRG proteins were displayed on two-dimensional gels and analyzed through quantitative densitometry, statistical validation of the quantitative data, and peptide mass fingerprinting for protein identification. Among ≈1,300 protein spots detected on each gel, we discovered 67 proteins that were tightly regulated by nerve ligation. We find that the injury to primary sensory neurons turned on multiple cellular mechanisms critical for the structural and functional integrity of neurons and for the defense against oxidative damage. Our data indicate that the regulation of metabolic enzymes was carefully orchestrated to meet the altered energy requirement of the DRG cells. Our data also demonstrate that ligation of the L5 spinal nerve led to the upregulation in the L4 DRG of the proteins that are highly expressed in embryonic sensory neurons. To understand the molecular mechanisms underlying neuropathic pain, we need to comprehend such dynamic aspect of protein modulations that follow nerve injury.

scholarly journals Three-dimensional analysis of the characteristics of joint motion and gait pattern in a rodent model following spinal nerve ligation

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Takayuki Seto ◽  
Hidenori Suzuki ◽  
Tomoya Okazaki ◽  
Yasuaki Imajo ◽  
Norihiro Nishida ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pain Intensity ◽  
Rat Model ◽  
Gait Pattern ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Joint Motion ◽  
Behavioral Reactions ◽  
Post Operation ◽  
The Right

Abstract Background The spinal nerve ligation (SNL) rat is well known as the most common rodent model of neuropathic pain without motor deficit. Researchers have performed analyses using only the von Frey and thermal withdrawal tests to evaluate pain intensity in the rat experimental model. However, these test are completely different from the neurological examinations performed clinically. We think that several behavioral reactions must be observed following SNL because the patients with neuropathic pain usually have impaired coordination of the motions of the right–left limbs and right–left joint motion differences. In this study, we attempted to clarify the pain behavioral reactions in SNL rat model as in patients. We used the Kinema-Tracer system for 3D kinematics gait analysis to identify new characteristic parameters of each joint movement and gait pattern. Results The effect of SNL on mechanical allodynia was a 47 ± 6.1% decrease in the withdrawal threshold during 1–8 weeks post-operation. Sagittal trajectories of the hip, knee and ankle markers in SNL rats showed a large sagittal fluctuation of each joint while walking. Top minus bottom height of the left hip and knee that represents instability during walking was significantly larger in the SNL than sham rats. Both-foot contact time, which is one of the gait characteristics, was significantly longer in the SNL versus sham rats: 1.9 ± 0.15 s vs. 1.03 ± 0.15 s at 4 weeks post-operation (p = 0.003). We also examined the circular phase time to evaluate coordination of the right and left hind-limbs. The ratio of the right/left circular time was 1.0 ± 0.08 in the sham rats and 0.62 ± 0.15 in the SNL rats at 4 weeks post-operation. Conclusions We revealed new quantitative parameters in an SNL rat model that are directly relevant to the neurological symptoms in patients with neuropathic pain, in whom the von Frey and thermal withdrawal tests are not used at all clinically. This new 3D analysis system can contribute to the analysis of pain intensity of SNL rats in detail similar to human patients’ reactions following neuropathic pain.

scholarly journals Oral Gabapentin Activates Spinal Cholinergic Circuits to Reduce Hypersensitivity after Peripheral Nerve Injury and Interacts Synergistically with Oral Donepezil

2007 ◽  
Vol 106 (6) ◽  
pp. 1213-1219 ◽  
Author(s):  
Ken-ichiro Hayashida ◽  
Renée Parker ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Intrathecal Injection ◽  
Spinal Nerve ◽  
Male Rats ◽  
Additive Interaction ◽  
Alzheimer Dementia ◽  
Routes Of Administration ◽  
Withdrawal Threshold ◽  
The Brain

Background Gabapentin administration into the brain of mice reduces nerve injury-induced hypersensitivity and is blocked by intrathecal atropine and enhanced by intrathecal neostigmine. The authors tested the relevance of these findings to oral therapy by examining the efficacy of oral gabapentin to reduce hypersensitivity after nerve injury in rats and its interaction with the clinically used cholinesterase inhibitor, donepezil. Methods Male rats with hypersensitivity after spinal nerve ligation received gabapentin orally, intrathecally, and intracerebroventricularly with or without intrathecal atropine, and withdrawal threshold to paw pressure was determined. The effects of oral gabapentin and donepezil alone and in combination on withdrawal threshold were determined in an isobolographic design. Results Gabapentin reduced hypersensitivity to paw pressure by all routes of administration, and was more potent and with a quicker onset after intracerebroventricular than intrathecal injection. Intrathecal atropine reversed the effect of intracerebroventricular and oral gabapentin. Oral gabapentin and donepezil interacted in a strongly synergistic manner, with an observed efficacy at one tenth the predicted dose of an additive interaction. The gabapentin-donepezil combination was reversed by intrathecal atropine. Conclusions Although gabapentin may relieve neuropathic pain by actions at many sites, these results suggest that its actions in the brain to cause spinal cholinergic activation predominate after oral administration. Side effects, particularly nausea, cannot be accurately determined on rats. Nevertheless, oral donepezil is well tolerated by patients in the treatment of Alzheimer dementia, and the current study provides the rationale for clinical study of combination of gabapentin and donepezil to treat neuropathic pain.

scholarly journals Nefopam downregulates autophagy and c-Jun N-terminal kinase activity in the regulation of neuropathic pain development following spinal nerve ligation

2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Seon-Hee Oh ◽  
Myung Ha Yoon ◽  
Kyung Joon Lim ◽  
Byung Sik Yu ◽  
In Gook Jee ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Kinase Activity ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation
Sign in / Sign up

Export Citation Format

Share Document